Hydroxyphenylpropanolamine hydrochloride



Patented Mar. 26, 1935 UNITED STATES.

HYDROXYPHENYLPROPANOLAMINE HYDROCHLORIDE Walter H. Hartung, Baltimore,Md., assignor to ,Sharp & Dohme, Incorporated, Philadelphia,

Pa., a corporation of Maryland No Drawing. Application September 22,1931, 7 Serial No. 564,473

14 Claims. (Cl. 260-1285) This invention relates to-certain novel andvaluablexchemical products, namely the monohydroxyphenylpropanolamineswhich are prepared in the form of their salts. In my co-pendingapplication Serial No. 360,005, filed May 2, 1929, of which this is inpart a continuation,. I have described the newparahydroxyphenylpropanolamine hydrochloride and the method of preparingit by reacting parahydroxyphenylethyl ketone with butyl nitrite and thenreducing the parahydroxyphenyloximinoethyl ketone thus formed. I havenow found that the metahydroxyphenylpropanolamine hydro chloride can beprepared by a'similar processg although with somewhat more difiiculty.

Parahydroxyphenylpropanolalnine hydrochlorideMetahydroxyphenylpropanolamine hydrochloride These new compounds arevaluable therapeutic agents. They. are useful in increasing the bloodpressure and in reducing the congestionin such tissues as the nasalmucosa appearing in such conditions as common colds and hay fever.

The para compound may be prepared in the following manner: 90 parts ofparahydroxyphenylethyl ketone, O=C(CeI-I4-OH) C2H5, are dissolved orsuspended in about 400 parts of ether. Hydrogen chloride is slowlybubbled thru the solution or suspension while agitating it, and 61.8grams of butyl nitrite is added during the course of sixty to ninetyminutes. During the addition of the butyl nitrite the suspended ketonegradually dissolves. The solution is allowed to stand for at least anhour, but preferably over night, when it is repeatedly extracted withdilute alkali until allalkali-soluble material. is removed. The alkalineextract is slowly acidified and the precipitate which forms is crudeparahydroxyphenylalphaoximinoethyl ketone, O=C(CeH4 OH) --CH(NOH)-CH3.This after recrystallization from water melts at 185 C.

10.8 parts of the oximinoethylketone thus prepared is dissolved in about125 parts of absolute alcohol containing 5.6 parts of hydrogen chloride.The solution in an atmosphere of hydrogen is agitated with a catalystcomposed of palladium supported on charcoal prepared by agitating a pureanimal charcoal in an aqueous solution of palladium chloride in anatmosphere of hydrogen in the proportions of about one part of palladiumchloride to six parts ofcharcoal. The agitation of the alcohol solutionwith the catalyst is continued until no more hydrogen is absorbed. Thisrequires from to minutes. When reduction is complete the catalyst isfiltered off and the filtrate evaporated to dryness at ordinarytemperature in a desiccator. The residue is the hydrochloride ofparahydroxyphenylalphaaminoethyl ketone, 0=C CeH4-OH) CI-I (NI-12.1161)CH3. 7 This is dissolved in 200 parts of water and agitated with thepalladiumcatalyst in an atmosphere of hydrogen until saturated. Theproduct which'is recovered from the solution is the hydrochloride ofparahydroxyphenylpropanolamine, which, after recrystallization fromabsolutealcohol, melts at 206.5 C.

The corresponding free base has the following formula: I

It can be prepared by treating the hydrochloride with ammonia.

Instead of preparing the aminoethylketone and then reducing it, asdescribed above and in my co-pending application, the oximinoethylketonemay be reduced directly to the alcohol in a single operation. g

The hydrochloride of the metahydroxyphenylpropanolamine maybe preparedby dissolving or suspending 90 parts of metahydroxyphenylethyl ketone, O=C(CsI-I4-OH)C2H5, in about 00 parts of ether. Hydrogen chloride isslowly bubbled thru the solution or suspension while agitating it and61.8 grams of butyl nitrite is added during the course of sixty toninety minutes.

During the addition of the butyl nitrite the suspendedmetahydroxyphenylethyl ketone gradually dissolves. The mixture orsolution is allowed to stand for at least an hour, but preferably overnight. It is then repeatedly extracted with dilute alkali until allalkali-soluble material is removed. The alkaline extract is slowlyacidified and the precipitate which forms is crudemetahydroxyphenylalphaoximinoethyl ketone. After recrystallization fromWater this melts at 138 C.

10.8 parts of this meta ketone is dissolved in about parts of absolutealcohol containing 5.6 parts of hydrogen chloride. The solution isagitated with a catalyst such as the palladium catalyst above describedin an atmosphere of hydrogen until no more hydrogen is absorbed. Thisrequires from to minutes or more. When reduction is complete thecatalyst is filtered off and the filtrate evaporated to dryness by beingplaced in a desiccator at ordinary temperature. The residue is thehydrochloride of metahydroxyphenylalphaaminoethyl ketone. This ispurified by recrystallization from absolute alcohol. It is thendissolved in 200 parts of water and agitated with a further quantity ofthe palladium catalyst in an atmosphere of hydrogen until saturated. Theproduct thus recovered from the solution is the hydrochloride ofmetahydroxyphenylpropanol amine. After recrystallization from absolutealcohol this melts at 177 C.

The corresponding free base has the following formula:

It can be prepared from the hydrochloride by treatment with ammonia.

The invention is not limited to the production of the new compounds bythe methods disclosed.

I claim:

1. As new products monohydroxyphenylpropanolamine hydrochlorides.

2. As a new product parahydroxyphenylpropanolamine hydrochloride.

3. As a new product metahydroxyphenylpropanolamine hydrochloride.

4. A monohydroxyphenylpropanolamine hydrochloride of sufiicient purityto be used ther-' apeutically.

5. Parahydroxyphenylpropanolamine hydrochloride of sufficient purity tobe used therapeutically.

6. Metahydroxyphenylpropanolamine hydrochloride of sufficient purity tobe used therapeutically.

'7. The process which consists in causing nitrous acid to act upon acompound of the following formula wherein at least one X stands forhydroxy, the other for hydrogen, n being 1 or a multiple thereof, andreducing the isonitroso compound thus obtained.

8. The process which consists in causing mtrous acid to act upon acompound of the following formula xOoo-cmorn l xOoo-orn-om wherein atleast one X stands for hydroxy, the other for hydrogen and reducing theisonitroso compound thus obtained, by means of hydrogen in presence of ahydrogenation catalyst.

10. The process which consists in causing butyl nitrite and a strongmineral acid to act upon para-hydroxy-prop;iophenone and reducing thepara-hydroxy-isonitrosopropiophenone thus obtained by means of hydrogenin presence of a hydrogenation catalyst.

11. The process which consists in causing butyl nitrite and a strongmineral acid to act upon meta-hydroxy-propiophenone and reducing themeta-hydroxy-isonitroso-propiophenone thus obtained by means of hydrogenin presence of a hydrogenation catalyst.

12. As new products, the compounds of the following formula wherein oneX stands for hydroxy, the other for hydrogen.

13. As a new product, the compound of the following formula thehydrochloride of which melts at 207 C.

14. As a new product, the compound of the following formula thehydrochloride of which melts at 180 C.

WALTER H. HARTUNG.

